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Liu YL, Mei YM, Xun JQ, Lv ZY, He Q, Liu ZBR, Li L, Xie F, Dai RC. The biological function of integrin-linked kinase on bone formation. Bone Rep 2025; 25:101834. [PMID: 40171447 PMCID: PMC11957501 DOI: 10.1016/j.bonr.2025.101834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 01/30/2025] [Accepted: 03/08/2025] [Indexed: 04/03/2025] Open
Abstract
Bone remodeling process is the basis for maintaining normal bone microstructure and promoting fracture repair. Recent studies have proven that integrins can promote bone formation and fracture repair. Integrin-linked kinase (ILK), as the proximal effector of the integrin receptor, is a key protein factor linking integrin and cytoskeleton. It is involved in crucial cellular processes including proliferation, survival, differentiation, migration, invasion, and angiogenesis reflects on systemic changes in the kidney, heart, muscle, skin, and vascular system. At present, the regulation effect of ILK in bone formation attracts the attention of researchers. This review emphasizes that ILK as a key molecule affects the functions of bone marrow stromal cells (BMSCs) and osteoblasts, and regulates bone formation. Additionally, ILK plays a key role in the process of"angiogenic-osteogenic coupling ". The present role of ILK in the pathogenesis of osteoporosis is also described. Strategies that target ILK may as a new prospective treatment for osteoporosis (OP).
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Affiliation(s)
- Yu-ling Liu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yue-ming Mei
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jing-qiong Xun
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Zhuo-yue Lv
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Qian He
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Zhou-bo-ran Liu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Lin Li
- Department of Endocrinology and Metabolism, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha 410005, Hunan, China
| | - Fen Xie
- Medicine School, Changsha Social Work College, Changsha 410004, Hunan, China
| | - Ru-chun Dai
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
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Shao L, Wang Q, Chen B, Zheng Y. The Roles and Molecular Mechanisms of HIF-1α in Pulpitis. J Dent Res 2025:220345251320970. [PMID: 40102725 DOI: 10.1177/00220345251320970] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025] Open
Abstract
Pulpitis is characterized by inflammation within dental pulp tissue, primarily triggered by bacterial infection. Hypoxia-inducible factor-1α (HIF-1α), a key transcriptional regulator, is stabilized under the hypoxic conditions associated with pulpitis. This review examines the roles and molecular mechanisms of HIF-1α in the pathogenesis and progression of pulpitis. Hypoxia in pulpitis prevents the degradation of HIF-1α, leading to its elevated expression. Furthermore, lipopolysaccharide from invading bacteria upregulates HIF-1α transcription through nuclear factor kappa B and mitogen-activated protein kinase pathways. HIF-1α regulates immunity and pulp remodeling in a stage-dependent manner by controlling various cytokines. During the inflammation stage, HIF-1α promotes recruitment of neutrophils and enhances their bactericidal effects by facilitating neutrophil extracellular trap release and M1 macrophage polarization. Concurrently, HIF-1α contributes to programmed cell death by increasing mitophagy. In the proliferation stage, HIF-1α stimulates immune responses involving T cells and dendritic cells. In the remodeling stage, HIF-1α supports angiogenesis and pulp-dentin regeneration. However, excessive pulpitis-induced hypoxia may disrupt vascular dynamics within the pulp chamber. This disruption highlights a critical threshold for HIF-1α, beyond which its effects might accelerate pulp necrosis. Overall, HIF-1α plays a central role in regulating immunity and tissue remodeling during pulpitis. A comprehensive understanding of the physiological and pathological roles of HIF-1α is essential for the advancement of effective strategies to manage irreversible pulpitis.
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Affiliation(s)
- L Shao
- Capital Medical University School of Stomatology, Beijing, China
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Q Wang
- Department of Stomatology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Capital Medical University School of Stomatology, Beijing, China
| | - B Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Y Zheng
- Department of Stomatology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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3
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Huchede P, Meyer S, Berthelot C, Hamadou M, Bertrand-Chapel A, Rakotomalala A, Manceau L, Tomine J, Lespinasse N, Lewandowski P, Cordier-Bussat M, Broutier L, Dutour A, Rochet I, Blay JY, Degletagne C, Attignon V, Montero-Carcaboso A, Le Grand M, Pasquier E, Vasiljevic A, Gilardi-Hebenstreit P, Meignan S, Leblond P, Ribes V, Cosset E, Castets M. BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas. eLife 2024; 12:RP91313. [PMID: 39373720 PMCID: PMC11458179 DOI: 10.7554/elife.91313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2024] Open
Abstract
Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell, and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.
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Affiliation(s)
- Paul Huchede
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Swann Meyer
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Clement Berthelot
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Maud Hamadou
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Adrien Bertrand-Chapel
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Andria Rakotomalala
- University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER Cancer Heterogeneity Plasticity and Resistance to Therapies, Centre Oscar LambretLilleFrance
| | - Line Manceau
- Université Paris Cité, CNRS, Institut Jacques MonodParisFrance
| | - Julia Tomine
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Nicolas Lespinasse
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Paul Lewandowski
- University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER Cancer Heterogeneity Plasticity and Resistance to Therapies, Centre Oscar LambretLilleFrance
| | - Martine Cordier-Bussat
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Laura Broutier
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Aurelie Dutour
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Isabelle Rochet
- Multisite Institute of Pathology, Groupement Hospitalier Est du CHU de Lyon, Hôpital Femme-Mère EnfantBronFrance
| | - Jean-Yves Blay
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | | | | | - Angel Montero-Carcaboso
- Preclinical Therapeutics and Drug Delivery Research Program, Department of Oncology, Hospital Sant Joan de DéuBarcelonaSpain
| | - Marion Le Grand
- Centre de Recherche en Cancérologie de Marseille (CRCM), Université Aix-Marseille, Institut Paoli- Calmettes, Centre de Lutte Contre le Cancer de la région PACA, INSERM 1068, CNRS 7258MarseilleFrance
| | - Eddy Pasquier
- Centre de Recherche en Cancérologie de Marseille (CRCM), Université Aix-Marseille, Institut Paoli- Calmettes, Centre de Lutte Contre le Cancer de la région PACA, INSERM 1068, CNRS 7258MarseilleFrance
| | - Alexandre Vasiljevic
- Multisite Institute of Pathology, Groupement Hospitalier Est du CHU de Lyon, Hôpital Femme-Mère EnfantBronFrance
| | | | - Samuel Meignan
- University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER Cancer Heterogeneity Plasticity and Resistance to Therapies, Centre Oscar LambretLilleFrance
| | - Pierre Leblond
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
- Department of Pediatric Oncology, Institute of Pediatric Hematology and Oncology (IHOPe), Centre Léon BérardLyonFrance
| | - Vanessa Ribes
- Université Paris Cité, CNRS, Institut Jacques MonodParisFrance
| | - Erika Cosset
- GLIMMER Of lIght (GLIoblastoma MetabolisM, HetERogeneity, and OrganoIds) team, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
| | - Marie Castets
- Childhood Cancer & Cell Death (C3) team, LabEx DEVweCAN, Institut Convergence Plascan, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286LyonFrance
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Zhaxi Q, Gesang L, Huang J, Suona Y, Ci B, Danzeng Z, Zhang R, Liu B. Hypermethylation of BMPR2 and TGF-β Promoter Regions in Tibetan Patients with High-Altitude Polycythemia at Extreme Altitude. Biochem Genet 2024:10.1007/s10528-024-10798-2. [PMID: 38787494 DOI: 10.1007/s10528-024-10798-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 04/01/2024] [Indexed: 05/25/2024]
Abstract
Although the expression of many genes is associated with adaptation to high-altitude hypoxic environments, the role of epigenetics in the response to this harsh environmental stress is currently unclear. We explored whether abnormal DNA promoter methylation levels of six genes, namely, ABCA1, SOD2, AKT1, VEGFR2, TGF-β, and BMPR2, affect the occurrence and development of high-altitude polycythemia (HAPC) in Tibetans. The methylation levels of HAPC and the control group of 130 Tibetans from very high altitudes (> 4500 m) were examined using quantitative methylation-specific real-time PCR (QMSP). Depending on the type of data, the Pearson chi-square test, Wilcoxon rank-sum test, and Fisher exact test were used to assess the differences between the two groups. The correlation between the methylation levels of each gene and the hemoglobin content was explored using a linear mixed model. Our experiment revealed that the methylation levels of the TGF-β and BMPR2 genes differed significantly in the two groups (p < 0.05) and linear mixed model analysis showed that the correlation between the hemoglobin and methylation of ABCA1, TGF-β, and BMPR2 was statistically significant (p < 0.05). Our study suggests that levels of TGF-β and BMPR2 methylation are associated with the occurrence of HAPC in extreme-altitude Tibetan populations among 6 selected genes. Epigenetics may be involved in the pathogenesis of HAPC, and future experiments could combine gene and protein levels to verify the diagnostic value of TGF-β and BMPR2 methylation levels in HAPC.
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Affiliation(s)
- Quzong Zhaxi
- Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital, 18 Linkuo North Road, Chengguan District, Lhasa, Tibet Autonomous Region, People's Republic of China
| | - Luobu Gesang
- Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital, 18 Linkuo North Road, Chengguan District, Lhasa, Tibet Autonomous Region, People's Republic of China.
| | - Ju Huang
- Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital, 18 Linkuo North Road, Chengguan District, Lhasa, Tibet Autonomous Region, People's Republic of China
| | - Yangzong Suona
- Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital, 18 Linkuo North Road, Chengguan District, Lhasa, Tibet Autonomous Region, People's Republic of China
| | - Bai Ci
- Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital, 18 Linkuo North Road, Chengguan District, Lhasa, Tibet Autonomous Region, People's Republic of China
| | - Zhuoga Danzeng
- Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital, 18 Linkuo North Road, Chengguan District, Lhasa, Tibet Autonomous Region, People's Republic of China
| | - Rui Zhang
- Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital, 18 Linkuo North Road, Chengguan District, Lhasa, Tibet Autonomous Region, People's Republic of China
| | - Binyun Liu
- Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital, 18 Linkuo North Road, Chengguan District, Lhasa, Tibet Autonomous Region, People's Republic of China
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Berthelot C, Huchedé P, Bertrand-Chapel A, Beuriat PA, Leblond P, Castets M. Bone Morphogenic Proteins in Pediatric Diffuse Midline Gliomas: How to Make New Out of Old? Int J Mol Sci 2024; 25:3361. [PMID: 38542334 PMCID: PMC10969837 DOI: 10.3390/ijms25063361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/06/2024] [Accepted: 03/11/2024] [Indexed: 11/11/2024] Open
Abstract
The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients. The epigenetic remodeling associated with these genetic alterations has also been precisely described, creating a permissive context for oncogenic transcriptional program activation. This review aims to describe the new findings about the involvement of BMP pathway activation in these tumors, placing their appearance in a developmental context. Targeting the oncogenic synergy resulting from this pathway activation in an H3K27M context could offer new therapeutic perspectives based on targeting treatment-resistant cell states.
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Affiliation(s)
- Clément Berthelot
- Childhood Cancer & Cell Death Team (C3 Team), LabEx DEVweCAN, Institut Convergence Plascan, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008 Lyon, France; (C.B.); (P.H.); (A.B.-C.); (P.L.); (M.C.)
- South-ROCK Pediatric Cancer Research Center, 69008 Lyon, France
| | - Paul Huchedé
- Childhood Cancer & Cell Death Team (C3 Team), LabEx DEVweCAN, Institut Convergence Plascan, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008 Lyon, France; (C.B.); (P.H.); (A.B.-C.); (P.L.); (M.C.)
- South-ROCK Pediatric Cancer Research Center, 69008 Lyon, France
| | - Adrien Bertrand-Chapel
- Childhood Cancer & Cell Death Team (C3 Team), LabEx DEVweCAN, Institut Convergence Plascan, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008 Lyon, France; (C.B.); (P.H.); (A.B.-C.); (P.L.); (M.C.)
- South-ROCK Pediatric Cancer Research Center, 69008 Lyon, France
| | - Pierre-Aurélien Beuriat
- South-ROCK Pediatric Cancer Research Center, 69008 Lyon, France
- Multisite Institute of Pathology, Groupement Hospitalier Est du CHU de Lyon, Hopital Femme-Mère-Enfant, 69677 Bron, France
| | - Pierre Leblond
- Childhood Cancer & Cell Death Team (C3 Team), LabEx DEVweCAN, Institut Convergence Plascan, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008 Lyon, France; (C.B.); (P.H.); (A.B.-C.); (P.L.); (M.C.)
- South-ROCK Pediatric Cancer Research Center, 69008 Lyon, France
- Department of Translational Research in Pediatric Oncology PROSPECT, Centre Léon Bérard, 69008 Lyon, France
- Department of Pediatric Oncology, Institut d’Hématologie et d’Oncologie Pédiatrique, Centre Léon Bérard, 69008 Lyon, France
| | - Marie Castets
- Childhood Cancer & Cell Death Team (C3 Team), LabEx DEVweCAN, Institut Convergence Plascan, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69008 Lyon, France; (C.B.); (P.H.); (A.B.-C.); (P.L.); (M.C.)
- South-ROCK Pediatric Cancer Research Center, 69008 Lyon, France
- Department of Translational Research in Pediatric Oncology PROSPECT, Centre Léon Bérard, 69008 Lyon, France
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Wang H, Kaplan FS, Pignolo RJ. The HIF-1α and mTOR Pathways Amplify Heterotopic Ossification. Biomolecules 2024; 14:147. [PMID: 38397384 PMCID: PMC10887042 DOI: 10.3390/biom14020147] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/16/2024] [Accepted: 01/23/2024] [Indexed: 02/25/2024] Open
Abstract
Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (ACVR1, also known as ALK2) gene. FOP is characterized by episodic heterotopic ossification (HO) in skeletal muscles, tendons, ligaments, or other soft tissues that progressively causes irreversible loss of mobility. FOP mutations cause mild ligand-independent constitutive activation as well as ligand-dependent bone morphogenetic protein (BMP) pathway hypersensitivity of mutant ACVR1. BMP signaling is also a key pathway for mediating acquired HO. However, HO is a highly complex biological process involving multiple interacting signaling pathways. Among them, the hypoxia-inducible factor (HIF) and mechanistic target of rapamycin (mTOR) pathways are intimately involved in both genetic and acquired HO formation. HIF-1α inhibition or mTOR inhibition reduces HO formation in mouse models of FOP or acquired HO in part by de-amplifying the BMP pathway signaling. Here, we review the recent progress on the mechanisms of the HIF-1α and mTOR pathways in the amplification of HO lesions and discuss the future directions and strategies to translate the targeting of HIF-1α and the mTOR pathways into clinical interventions for FOP and other forms of HO.
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Affiliation(s)
- Haitao Wang
- Department of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Frederick S. Kaplan
- Department of Orthopaedic Surgery, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Medicine, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA
- The Center for Research in FOP and Related Disorders, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert J. Pignolo
- Department of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Medicine, Divisions of Endocrinology, Hospital Internal Medicine, Rochester, MN 55905, USA
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Huang YC, Chen WC, Yu CL, Chang TK, I-Chin Wei A, Chang TM, Liu JF, Wang SW. FGF2 drives osteosarcoma metastasis through activating FGFR1-4 receptor pathway-mediated ICAM-1 expression. Biochem Pharmacol 2023; 218:115853. [PMID: 37832794 DOI: 10.1016/j.bcp.2023.115853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 09/25/2023] [Accepted: 10/10/2023] [Indexed: 10/15/2023]
Abstract
Osteosarcoma is a malignant tumor with high metastatic potential, such that the overall 5-year survival rate of patients with metastatic osteosarcoma is only 20%. Therefore, it is necessary to unravel the mechanisms of osteosarcoma metastasis to identify predictors of metastasis by which to develop new therapies. Fibroblast growth factor 2 (FGF2) is a growth factor involved in embryonic development, cell migration, and proliferation. The overexpression of FGF2 and FGF receptors (FGFRs) has been shown to enhance cancer cell proliferation in lung, breast, gastric, and prostate cancers as well as melanoma. Nonetheless, the roles of FGF2 and FGFRs in human osteosarcoma cells remain unknown. In the present study, we found that FGF2 was overexpressed in human osteosarcoma sections and correlated with lung metastasis. Treatment of FGF2 induced migration activity, invasion activity, and intercellular adhesion molecule (ICAM)-1 expression in osteosarcoma cells. In particular, the downregulation or antagonism of FGFR1-4 suppressed FGF2-induced ICAM-1 expression and cancer cell migration. Furthermore, FGFR1, FGFR2, FGFR3, and FGFR4 were involved in FGF2-induced the phospholipase Cβ/protein kinase Cα/proto-oncogene c-Src signaling pathway and triggered c-Jun nuclear translocation. Subsequent c-Jun upregulation of activator protein-1 transcription activity on the ICAM-1 promoter led to an increased migration of osteosarcoma cells. Moreover, the knockdown of endogenous FGF2 suppressed ICAM-1 expression and migration of osteosarcoma cells. These findings suggest that FGF2/FGFR1-4 signaling promotes metastasis via its direct downstream target gene ICAM-1, revealing a novel potential therapeutic target for osteosarcoma.
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Affiliation(s)
- Yu-Ching Huang
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan; Division of Spine Surgery, Department of Orthopedic Surgery, MacKay Memorial Hospital, Taipei, Taiwan
| | - Wei-Cheng Chen
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; Division of Sports Medicine & Surgery, Department of Orthopedic Surgery, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chen-Lin Yu
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan
| | - Ting-Kuo Chang
- Division of Spine Surgery, Department of Orthopedic Surgery, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Augusta I-Chin Wei
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Tsung-Ming Chang
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Ju-Fang Liu
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
| | - Shih-Wei Wang
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
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8
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Wang J, Zhao B, Che J, Shang P. Hypoxia Pathway in Osteoporosis: Laboratory Data for Clinical Prospects. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:3129. [PMID: 36833823 PMCID: PMC9963321 DOI: 10.3390/ijerph20043129] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/02/2023] [Accepted: 02/04/2023] [Indexed: 05/29/2023]
Abstract
The hypoxia pathway not only regulates the organism to adapt to the special environment, such as short-term hypoxia in the plateau under normal physiological conditions, but also plays an important role in the occurrence and development of various diseases such as cancer, cardiovascular diseases, osteoporosis. Bone, as a special organ of the body, is in a relatively low oxygen environment, in which the expression of hypoxia-inducible factor (HIF)-related molecules maintains the necessary conditions for bone development. Osteoporosis disease with iron overload endangers individuals, families and society, and bone homeostasis disorder is linked to some extent with hypoxia pathway abnormality, so it is urgent to clarify the hypoxia pathway in osteoporosis to guide clinical medication efficiently. Based on this background, using the keywords "hypoxia/HIF, osteoporosis, osteoblasts, osteoclasts, osteocytes, iron/iron metabolism", a matching search was carried out through the Pubmed and Web Of Science databases, then the papers related to this review were screened, summarized and sorted. This review summarizes the relationship and regulation between the hypoxia pathway and osteoporosis (also including osteoblasts, osteoclasts, osteocytes) by arranging the references on the latest research progress, introduces briefly the application of hyperbaric oxygen therapy in osteoporosis symptoms (mechanical stimulation induces skeletal response to hypoxic signal activation), hypoxic-related drugs used in iron accumulation/osteoporosis model study, and also puts forward the prospects of future research.
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Affiliation(s)
- Jianping Wang
- School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Bin Zhao
- School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Jingmin Che
- School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Peng Shang
- School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research & Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen 518057, China
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9
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Tao J, Miao R, Liu G, Qiu X, Yang B, Tan X, Liu L, Long J, Tang W, Jing W. Spatiotemporal correlation between HIF-1α and bone regeneration. FASEB J 2022; 36:e22520. [PMID: 36065633 DOI: 10.1096/fj.202200329rr] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 08/04/2022] [Accepted: 08/15/2022] [Indexed: 12/20/2022]
Abstract
Hypoxia-inducible factors (HIFs) are core regulators of the hypoxia response. HIF signaling is activated in the local physiological and pathological hypoxic environment, acting on downstream target genes to synthesize the corresponding proteins and regulate the hypoxic stress response. HIFs belong to the hypoxia-activated transcription family and contain two heterodimeric transcription factors, HIF-α and HIF-β. Under hypoxia, the dimer formed by HIF-α binding to HIF-β translocates into the nucleus and binds to the hypoxia response element (HRE) to induce transcription of a series of genes. HIF-1α plays an important role in innate bone development and acquired bone regeneration. HIF-1α promotes bone regeneration mainly through the following two pathways: (1) By regulating angiogenesis-osteoblast coupling to promote bone regeneration; and (2) by inducing metabolic reprogramming in osteoblasts, promoting cellular anaerobic glycolysis, ensuring the energy supply of osteoblasts under hypoxic conditions, and further promoting bone regeneration and repair. This article reviews recent basic research on HIF-1α and its role in promoting osteogenesis, discusses the possible molecular mechanisms, introduces the hypoxia-independent role of HIF-1α and reviews the application prospects of HIF-1α in tissue engineering.
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Affiliation(s)
- Junming Tao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Rong Miao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Gang Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiaoning Qiu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Baohua Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xinzhi Tan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lei Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jie Long
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wei Tang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wei Jing
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Spreadborough PJ, Strong AL, Mares J, Levi B, Davis TA. Tourniquet use following blast-associated complex lower limb injury and traumatic amputation promotes end organ dysfunction and amplified heterotopic ossification formation. J Orthop Surg Res 2022; 17:422. [PMID: 36123728 PMCID: PMC9484189 DOI: 10.1186/s13018-022-03321-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 09/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Traumatic heterotopic ossification (tHO) is characterized by ectopic bone formation in extra-skeletal sites leading to impaired wound healing, entrapment of neurovascular structures, pain, and reduced range of motion. HO has become a signature pathology affecting wounded military personnel who have sustained blast-associated traumatic amputations during the recent conflicts in Iraq and Afghanistan and can compound recovery by causing difficulty with prosthesis limb wearing. Tourniquet use to control catastrophic limb hemorrhage prior to surgery has become almost ubiquitous during this time, with the recognition the prolonged use may risk an ischemia reperfusion injury and associated complications. While many factors influence the formation of tHO, the extended use of tourniquets to limit catastrophic hemorrhage during prolonged field care has not been explored. METHODS Utilizing an established pre-clinical model of blast-associated complex lower limb injury and traumatic amputation, we evaluated the effects of tourniquet use on tHO formation. Adult male rats were subjected to blast overpressure exposure, femur fracture, and soft tissue crush injury. Pneumatic tourniquet (250-300 mmHg) applied proximal to the injured limb for 150-min was compared to a control group without tourniquet, before a trans-femoral amputation was performed. Outcome measures were volume to tHO formation at 12 weeks and changes in proteomic and genomic markers of early tHO formation between groups. RESULTS At 12 weeks, volumetric analysis with microCT imaging revealed a 70% increase in total bone formation (p = 0.007) near the site of injury compared to rats with no tourniquet time in the setting of blast-injuries. Rats subjected to tourniquet usage had increased expression of danger-associated molecular patterns (DAMPs) and end organ damage as early as 6 h and as late as 7 days post injury. The expressions of pro-inflammatory cytokines and chemokines and osteochondrogenic genes using quantitative RT-PCR similarly revealed increased expression as early as 6 h post injury, and these genes along with hypoxia associated genes remained elevated for 7 days compared to no tourniquet use. CONCLUSION These findings suggest that tourniquet induced ischemia leads to significant increases in key transcription factors associated with early endochondral bone formation, systemic inflammatory and hypoxia, resulting in increased HO formation.
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Affiliation(s)
- Philip J. Spreadborough
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 USA
- Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, UK
| | - Amy L. Strong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI USA
| | - John Mares
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 USA
| | - Benjamin Levi
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX USA
| | - Thomas A. Davis
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 USA
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11
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Zhang C, Liu YW, Chen M, Min S, Mao J, Li Q, Chi Z. CoCl 2 -simulated hypoxia potentiates the osteogenic differentiation of fibroblasts derived from tympanosclerosis by upregulating the expression of BMP-2. Cell Biol Int 2022; 46:1423-1432. [PMID: 35811437 DOI: 10.1002/cbin.11845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 02/20/2022] [Accepted: 03/15/2022] [Indexed: 11/08/2022]
Abstract
Tympanosclerosis (TS) is a result of long-standing middle ear inflammation characterized by fibroblasts ossification. Fibrosis is the last revertible stage in the progress of middle ear inflammation to TS. It was hypothesized that chronic hypoxia could be modulating fibrosis, which in turn additionally further aggravated hypoxia via decreasing oxygen diffusion. However, the effects of hypoxia on osteoinductive activity of fibroblasts have not been explored. Herein, we purposed to explore the role of hypoxia in osteogenic differentiation of fibroblasts derived from TS. The expression of bone morphogenetic protein-2 (BMP-2), hypoxia-inducible factor-1α (HIF-1α), and Vimentin in the human surgical specimens of tympansclerosis was investigated by immunofluorescent staining. Furthermore, cultured fibroblasts were stratified into the following study groups: control, 25, 50, and 100 μM cobaltous chloride (CoCl2 ) group. BMP-2, as well as HIF-1α levels of expression were detected via western blotting and immunofluorescence analysis. We found that the expression of BMP-2 and HIF-1α was significantly upregulated in TS tissues and these fibroblasts, which was vimentin positive surrounding sclerotic plaques, were also expressing HIF-1α positive. The results also demonstrated that CoCl2 treatment increased nuclear HIF-1α protein level in the fibroblast. Furthermore, treatment with CoCl2 significantly increased BMP-2 expression and remarkably elevated alkaline phosphatse activity and the mineralized nodules area. These data illustrate that hypoxia may play an osteogenic role in TS fibroblasts via the elevated expression of a possible osteogenic factor, BMP-2.
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Affiliation(s)
- Chen Zhang
- ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Yang-Wenyi Liu
- ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, PR China
| | - Min Chen
- ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, PR China
| | - Shiyao Min
- ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, PR China
| | - Jiabao Mao
- ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, PR China
| | - Qin Li
- Stomatology Department, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Zhangcai Chi
- ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, PR China
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12
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Zhao L, Law NC, Gomez NA, Son J, Gao Y, Liu X, de Avila JM, Zhu M, Du M. Obesity Impairs Embryonic Myogenesis by Enhancing BMP Signaling within the Dermomyotome. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2102157. [PMID: 34647690 PMCID: PMC8596142 DOI: 10.1002/advs.202102157] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/16/2021] [Indexed: 05/05/2023]
Abstract
Obesity during pregnancy leads to adverse health outcomes in offspring. However, the initial effects of maternal obesity (MO) on embryonic organogenesis have yet to be thoroughly examined. Using unbiased single-cell transcriptomic analyses (scRNA-seq), the effects of MO on the myogenic process is investigated in embryonic day 9.5 (E9.5) mouse embryos. The results suggest that MO induces systematic hypoxia, which is correlated with enhanced BMP signaling and impairs skeletal muscle differentiation within the dermomyotome (DM). The Notch-signaling effectors, HES1 and HEY1, which also act down-stream of BMP signaling, suppress myogenic differentiation through transcriptionally repressing the important myogenic regulator MEF2C. Moreover, the major hypoxia effector, HIF1A, enhances expression of HES1 and HEY1 and blocks myogenic differentiation in vitro. In summary, this data demonstrate that MO induces hypoxia and impairs myogenic differentiation by up-regulating BMP signaling within the DM, which may account for the disruptions of skeletal muscle development and function in progeny.
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Affiliation(s)
- Liang Zhao
- Nutrigenomics and Growth Biology LaboratoryDepartment of Animal Sciencesand School of Molecular BioscienceWashington State UniversityPullmanWA99164USA
- Department of Animal SciencesWashington State UniversityPullmanWA99164USA
| | - Nathan C. Law
- Department of Animal SciencesWashington State UniversityPullmanWA99164USA
- Center for Reproductive BiologyCollege of Veterinary MedicineWashington State UniversityPullmanWA99164USA
| | - Noe A. Gomez
- Nutrigenomics and Growth Biology LaboratoryDepartment of Animal Sciencesand School of Molecular BioscienceWashington State UniversityPullmanWA99164USA
- Department of Animal SciencesWashington State UniversityPullmanWA99164USA
| | - Junseok Son
- Nutrigenomics and Growth Biology LaboratoryDepartment of Animal Sciencesand School of Molecular BioscienceWashington State UniversityPullmanWA99164USA
- Department of Animal SciencesWashington State UniversityPullmanWA99164USA
| | - Yao Gao
- Nutrigenomics and Growth Biology LaboratoryDepartment of Animal Sciencesand School of Molecular BioscienceWashington State UniversityPullmanWA99164USA
- Department of Animal SciencesWashington State UniversityPullmanWA99164USA
| | - Xiangdong Liu
- Nutrigenomics and Growth Biology LaboratoryDepartment of Animal Sciencesand School of Molecular BioscienceWashington State UniversityPullmanWA99164USA
- Department of Animal SciencesWashington State UniversityPullmanWA99164USA
| | - Jeanene M. de Avila
- Nutrigenomics and Growth Biology LaboratoryDepartment of Animal Sciencesand School of Molecular BioscienceWashington State UniversityPullmanWA99164USA
- Department of Animal SciencesWashington State UniversityPullmanWA99164USA
| | - Mei‐Jun Zhu
- School of Food ScienceWashington State UniversityPullmanWA99164USA
| | - Min Du
- Nutrigenomics and Growth Biology LaboratoryDepartment of Animal Sciencesand School of Molecular BioscienceWashington State UniversityPullmanWA99164USA
- Department of Animal SciencesWashington State UniversityPullmanWA99164USA
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13
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Ko FC, Kobelski MM, Zhang W, Grenga GM, Martins JS, Demay MB. Phosphate restriction impairs mTORC1 signaling leading to increased bone marrow adipose tissue and decreased bone in growing mice. J Bone Miner Res 2021; 36:1510-1520. [PMID: 33900666 DOI: 10.1002/jbmr.4312] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 04/14/2021] [Accepted: 04/17/2021] [Indexed: 01/08/2023]
Abstract
Bone marrow stromal cells (BMSCs) are multipotent cells that differentiate into cells of the osteogenic and adipogenic lineage. A striking inverse relationship between bone marrow adipose tissue (BMAT) and bone volume is seen in several conditions, suggesting that differentiation of BMSCs into bone marrow adipocytes diverts cells from the osteogenic lineage, thereby compromising the structural and mechanical properties of bone. Phosphate restriction of growing mice acutely decreases bone formation, blocks osteoblast differentiation and increases BMAT. Studies performed to evaluate the cellular and molecular basis for the effects of acute phosphate restriction demonstrate that it acutely increases 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling in osteoblasts. This is accompanied by decreased expression of Wnt10b in BMSCs. Phosphate restriction also promotes expression of the key adipogenic transcription factors, peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer binding protein α (CEBPα), in CXCL12 abundant reticular (CAR) cells, which represent undifferentiated BMSCs and are the main source of BMAT and osteoblasts in the adult murine skeleton. Consistent with this, lineage tracing studies reveal that the BMAT observed in phosphate-restricted mice is of CAR cell origin. To determine whether circumventing the decrease in mTORC1 signaling in maturing osteoblasts attenuates the osteoblast and BMAT phenotype, phosphate-restricted mice with OSX-CreERT2 -mediated haploinsufficiency of the mTORC1 inhibitor, TSC2, were generated. TSC2 haploinsufficiency in preosteoblasts/osteoblasts normalized bone volume and osteoblast number in phosphate-restricted mice and attenuated the increase in BMAT observed. Thus, acute phosphate restriction leads to decreased bone and increases BMAT by impairing mTORC1 signaling in osterix-expressing cells. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Frank C Ko
- Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | | | - Wanlin Zhang
- Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Gina M Grenga
- Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Janaina S Martins
- Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Marie B Demay
- Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
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14
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Povoroznyuk VV, Dedukh NV, Bystrytska MA, Shapovalov VS. Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms. REGULATORY MECHANISMS IN BIOSYSTEMS 2021. [DOI: 10.15421/022130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This review provides a rationale for the cellular and molecular mechanisms of bone remodeling stages under physiological conditions and glucocorticoids (GCs) in excess. Remodeling is a synchronous process involving bone resorption and formation, proceeding through stages of: (1) resting bone, (2) activation, (3) bone resorption, (4) reversal, (5) formation, (6) termination. Bone remodeling is strictly controlled by local and systemic regulatory signaling molecules. This review presents current data on the interaction of osteoclasts, osteoblasts and osteocytes in bone remodeling and defines the role of osteoprogenitor cells located above the resorption area in the form of canopies and populating resorption cavities. The signaling pathways of proliferation, differentiation, viability, and cell death during remodeling are presented. The study of signaling pathways is critical to understanding bone remodeling under normal and pathological conditions. The main signaling pathways that control bone resorption and formation are RANK / RANKL / OPG; M-CSF – c-FMS; canonical and non-canonical signaling pathways Wnt; Notch; MARK; TGFβ / SMAD; ephrinB1/ephrinB2 – EphB4, TNFα – TNFβ, and Bim – Bax/Bak. Cytokines, growth factors, prostaglandins, parathyroid hormone, vitamin D, calcitonin, and estrogens also act as regulators of bone remodeling. The role of non-encoding microRNAs and long RNAs in the process of bone cell differentiation has been established. MicroRNAs affect many target genes, have both a repressive effect on bone formation and activate osteoblast differentiation in different ways. Excess of glucocorticoids negatively affects all stages of bone remodeling, disrupts molecular signaling, induces apoptosis of osteocytes and osteoblasts in different ways, and increases the life cycle of osteoclasts. Glucocorticoids disrupt the reversal stage, which is critical for the subsequent stages of remodeling. Negative effects of GCs on signaling molecules of the canonical Wingless (WNT)/β-catenin pathway and other signaling pathways impair osteoblastogenesis. Under the influence of excess glucocorticoids biosynthesis of biologically active growth factors is reduced, which leads to a decrease in the expression by osteoblasts of molecules that form the osteoid. Glucocorticoids stimulate the expression of mineralization inhibitor proteins, osteoid mineralization is delayed, which is accompanied by increased local matrix demineralization. Although many signaling pathways involved in bone resorption and formation have been discovered and described, the temporal and spatial mechanisms of their sequential turn-on and turn-off in cell proliferation and differentiation require additional research.
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15
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Yang J, Ueharu H, Mishina Y. Energy metabolism: A newly emerging target of BMP signaling in bone homeostasis. Bone 2020; 138:115467. [PMID: 32512164 PMCID: PMC7423769 DOI: 10.1016/j.bone.2020.115467] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/29/2020] [Accepted: 06/01/2020] [Indexed: 12/11/2022]
Abstract
Energy metabolism is the process of generating energy (i.e. ATP) from nutrients. This process is indispensable for cell homeostasis maintenance and responses to varying conditions. Cells require energy for growth and maintenance and have evolved to have multiple pathways to produce energy. Both genetic and functional studies have demonstrated that energy metabolism, such as glucose, fatty acid, and amino acid metabolism, plays important roles in the formation and function of bone cells including osteoblasts, osteocytes, and osteoclasts. Dysregulation of energy metabolism in bone cells consequently disturbs the balance between bone formation and bone resorption. Metabolic diseases have also been reported to affect bone homeostasis. Bone morphogenic protein (BMP) signaling plays critical roles in regulating the formation and function of bone cells, thus affecting bone development and homeostasis. Mutations of BMP signaling-related genes in mice have been reported to show abnormalities in energy metabolism in many tissues, including bone. In addition, BMP signaling correlates with critical signaling pathways such as mTOR, HIF, Wnt, and self-degradative process autophagy to coordinate energy metabolism and bone homeostasis. These findings will provide a newly emerging target of BMP signaling and potential therapeutic strategies and the improved management of bone diseases. This review summarizes the recent advances in our understanding of (1) energy metabolism in regulating the formation and function of bone cells, (2) function of BMP signaling in whole body energy metabolism, and (3) mechanistic interaction of BMP signaling with other signaling pathways and biological processes critical for energy metabolism and bone homeostasis.
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Affiliation(s)
- Jingwen Yang
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
| | - Hiroki Ueharu
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yuji Mishina
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
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16
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Yang WJ, Zhang GL, Cao KX, Liu XN, Wang XM, Yu MW, Li JP, Yang GW. Heparanase from triple‑negative breast cancer and platelets acts as an enhancer of metastasis. Int J Oncol 2020; 57:890-904. [PMID: 32945393 PMCID: PMC7473754 DOI: 10.3892/ijo.2020.5115] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/02/2020] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC), which is characterized by inherently aggressive behavior and lack of recognized molecular targets for therapy, poses a serious threat to women's health worldwide. However, targeted treatments have yet to be made available. A crosstalk between tumor cells and platelets (PLT) contributing to growth, angiogenesis and metastasis has been reported in numerous cancers. Heparanase (Hpa), the only mammalian endoglycosidase that cleaves heparan sulfate, has been demonstrated to contribute to the growth, angiogenesis and metastasis of numerous cancers. Hypoxia affects the growth, angiogenesis and metastasis of nearly all solid tumors, and the ability of Hpa to promote invasion is enhanced in hypoxia. However, whether Hpa can strengthen the crosstalk between tumor cells and PLT, and whether enhancing the biological function of Hpa in TNBC promotes malignant progression, have yet to be fully elucidated. The present study, based on bioinformatics analysis and experimental studies in vivo and in vitro, demonstrated that Hpa enhanced the crosstalk between TNBC cells and PLT to increase the supply of oxygen and nutrients, while also conferring tolerance of TNBC cells to oxygen and nutrient shortage, both of which are important for overcoming the stress of hypoxia and nutritional deprivation in the tumor microenvironment, thereby promoting malignant progression, including growth, angiogenesis and metastasis in TNBC. In addition, the hypoxia-inducible factor-1a (HIF-1a)/vascular endothelial growth factor-a (VEGF- a)/phosphorylated protein kinase B (p-)Akt axis may be the key pathway involved in the effects of Hpa on the biological processes mentioned above. Therefore, improving local hypoxia, anti-Hpa treatment and inhibiting PLT activation may improve the prognosis of TNBC.
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Affiliation(s)
- Wen-Jing Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, P.R. China
| | - Gan-Lin Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, P.R. China
| | - Ke-Xin Cao
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, P.R. China
| | - Xiao-Ni Liu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Xiao-Min Wang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, P.R. China
| | - Ming-Wei Yu
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, P.R. China
| | - Jin-Ping Li
- Biomedical Center, Uppsala University, Uppsala 75123, Sweden
| | - Guo-Wang Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, P.R. China
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Huang Y, Wang X, Lin H. The hypoxic microenvironment: a driving force for heterotopic ossification progression. Cell Commun Signal 2020; 18:20. [PMID: 32028956 PMCID: PMC7006203 DOI: 10.1186/s12964-020-0509-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 01/02/2020] [Indexed: 12/23/2022] Open
Abstract
Heterotopic ossification (HO) refers to the formation of bone tissue outside the normal skeletal system. According to its pathogenesis, HO is divided into hereditary HO and acquired HO. There currently lack effective approaches for HO prevention or treatment. A deep understanding of its pathogenesis will provide promising strategies to prevent and treat HO. Studies have shown that the hypoxia-adaptive microenvironment generated after trauma is a potent stimulus of HO. The hypoxic microenvironment enhances the stability of hypoxia-inducible factor-1α (HIF-1α), which regulates a complex network including bone morphogenetic proteins (BMPs), vascular endothelial growth factor (VEGF), and neuropilin-1 (NRP-1), which are implicated in the formation of ectopic bone. In this review, we summarize the current understanding of the triggering role and underlying molecular mechanisms of the hypoxic microenvironment in the initiation and progression of HO, focusing mainly on HIF-1 and it's influenced genes BMP, VEGF, and NRP-1. A better understanding of the role of hypoxia in HO unveils novel therapeutic targets for HO that reduce the local hypoxic microenvironment and inhibit HIF-1α activity.
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